tbuckley/cabot-search huggingface dataset:
MicroRNAs in circulating microvesicles and plasma as biomarkers that complement the clinical diagnosis of diabetic dyslipidemia and its complications
Authors: M Nemecz, DS Stefan, A Constantin, A Procopciuc, K Comarita, G Tanko, A Georgescu
Journal: Cardiovascular Research (2022)

Abstract Funding Acknowledgements Type of funding sources: Public grant(s) – National budget only. Main funding source(s): Research funded by grants of the Romanian Ministry of Education and Research, CNCS-UEFISCDI, project no. PN-III-P1-1.2-PCCDI-2017–0527 (Contract no. 83PCCDI/2018), project no. PN-III-P1-1.1-TE-2019–0811, within PNCDI III” (Contract no. TE 97/2020) Background Dislypidemia is a major risk factor for cardiovascular diseases as well as for diabetes where often leads to severe microvascular complications. Reportedly, microRNAs (miRNAs) associated with microvesicles (MVs) regulate cellular mechanisms in the progression of diabetic dyslipidemia. We hypothesised that detection of the changes in plasma MV components could be used as early biomarkers to prevent the irreversible effects of diabetic dyslipidemia. Purpose: of this study was to search whether in diabetic dyslipidemia with/without microvascular complications there are modifications of the circulating MVs and plasma miRNAs and whether these changes could be predictive of the disease evolution. Methods Plasma/sera was collected from diabetic patients with dyslipidemia with/without microvascular complications and the main parameters and the inflammatory markers were assessed. Results showed that, compared to either diabetes or dyslipidemia alone, in the diabetic dyslipidemic patients, significant increases in plasma glucose, cholesterol, LDL-cholesterol, triglyceride concentrations, systolic blood pressure were present. In addition, high levels of circulating IL-6 and MVs-derived from endothelial cells (CD144+), platelets (CD41+), macrophages (CD14+), and leucocytes (CD18+) were detected. Significant changes were found in plasma miRNAs and MV-associated miRNAs: 122,-132,-143,-200b,-212, decreased miR-34a,-155,-218 expressions in MVs, and reduced miR-21,-34a,-132,-143 expressions in plasma. Notably, when microvascular complications were associated to diabetic dyslipidemia, we found significant changes such as increased expression of miR-21,-34a,-122,-126,-143,-218,-223 in MV and plasma miR-143,-132 and decreased miR-200b,-212 in MVs and plasma miR-223. Conclusion In patients with diabetic dyslipidemia and, in particular, with diabetic dyslipidemia associated with microvascular complications, a significant modification in the plasma MV content and miRNAs occur suggesting that they could turn into biomarkers and potential diagnostic tool for diabetic dyslipidemia and its complications.
PRECISE CURATE.AI: A prospective feasibility trial to dynamically modulate personalized chemotherapy dose with artificial intelligence.
Authors: Agata Blasiak, Anh Truong, Wen Jeit, Lester Tan, Kirthika Senthil Kumar, Shi Bei Tan, Chong Boon Teo, Benjamin Kye Jyn Tan, Xavier Tadeo, Hon Lyn Tan, Cheng Ean Chee, Wei-Peng Yong, Dean Ho, Raghav Sundar
Journal: Journal of Clinical Oncology (2022)

1574 Background: Most treatment guidelines recommend chemotherapy at maximum tolerated doses, which does not always lead to optimal efficacy, but implicitly results in toxicity. To overcome this challenge, we developed CURATE.AI, a small data, AI-derived platform that harnesses only a patient’s own prospectively/longitudinally acquired data to dynamically identify their own optimal and personalized doses. We subsequently harnessed CURATE.AI to dynamically modulate individualized chemotherapy doses for patients in a prospective clinical trial. Methods: We conducted an open-label, multi-center, single-arm, prospective feasibility trial in patients diagnosed with advanced solid tumors and treated with single-agent capecitabine, XELOX or XELIRI (+/- biologics) (NCT04522284). The standard-of-care (SOC) capecitabine dose was 1000 mg/m 2 , unless adjusted by clinician to account for patient’s comorbidities and organ dysfunction. Using an AI-discovered second-order correlation between patient-specific variation of capecitabine doses and corresponding tumor marker (CEA, CA19-9 or CA-125) readouts for each cycle, CURATE.AI generated individualized patient digital avatars and recommended bespoke dose for the subsequent cycle. The clinicians were permitted to accept CURATE.AI dose recommendations, or reject the recommendations and dose based on clinical judgement. Results: Since August 2020 we recruited ten patients: single-agent capecitabine (n = 1), XELOX (n = 6), and XELIRI (n = 3). As of 20 Jan 2022, one patient remains on the trial. The prescribed dose was on average reduced by 20 % (± 13.8 %) as compared to the projected SOC dose. The nine reported patients completed 3.9 cycles (± 2.2 cycles), with the longest participation lasting 8 cycles. CURATE.AI recommendations were considered in 27 out of 40 total dosing decisions and accepted for prescription in 26 of those decisions. The reasons for not considering CURATE.AI included insufficient time from patient recruitment to the first dose administration and complex medical circumstances at the time of the dosing decisions. Conclusions: CURATE.AI has been successfully incorporated into the clinical workflow of dynamic dose selection in the treatment of solid tumors under a clinical trial. Prospective validation of CURATE.AI led to a reduction of an average prescribed capecitabine dose, which alongside additional preliminary findings may eventually play an important role in improving patient response rates and durations compared to SOC. Results from the PRECISE CURATE.AI trial support the initiation of a randomized clinical trial and potential expansion towards other oncologic indications. Clinical trial information: NCT04522284.
Idecabtagene vicleucel (Ide-cel) chimeric antigen receptor (CAR) T-cell therapy for relapsed/refractory multiple myeloma (RRMM): Real-world experience.
Authors: Doris K. Hansen, Surbhi Sidana, Lauren Peres, Leyla Shune, Douglas W. Sborov, Hamza Hashmi, Mehmet H. Kocoglu, Shebli Atrash, Gary Simmons, Nilesh Kalariya, Christopher J. Ferreri, Aimaz Afrough, Ankit J. Kansagra, Peter M. Voorhees, Melissa Alsina, Joseph McGuirk, Frederick L. Locke, Krina K. Patel
Journal: Journal of Clinical Oncology (2022)

8042 Background: Ide-cel, a BCMA directed CAR T-cell therapy, was FDA approved 3/26/2021 for the treatment of RRMM after 4 prior lines of therapy. We evaluated the real-world outcomes of patients treated with standard of care ide-cel under the commercial FDA label. Methods: Ten US academic centers contributed data to this effort independent of the manufacturer. As of 1/10/2022, 138 patients were leukapheresed with overall manufacturing failure in 6 (4%). 108 patients were infused ≥ 30 days prior to data-cut off and constitute the study population for this retrospective analysis. Results: Table describes the study population compared to the pivotal KarMMa-1 trial (Munshi et al, NEJM 2021). Patients in our study were less likely to have ECOG PS of 0/1 (77%) and more likely to be penta-refractory (41%). 67% of patients would not have met eligibility criteria for KarMMa. Common reasons for ineligibility (&gt; 1 reason in 22% patients) were co-morbidities (28%), cytopenias (22%), prior therapy with alloSCT/CAR-T/other BCMA therapy (19%), CNS myeloma/non-measurable disease/plasma cell leukemia (13%), and fitness (12%). 81% of patients received bridging therapy. Toxicity was comparable to that seen in KarMMa-1. Cytokine release syndrome (CRS) was seen in 82% (&gt; grade 3: 4%) and immune effector cell-associated neurotoxicity syndrome (ICANS) in 15% (&gt; grade 3: 5%) of patients, respectively. Tocilizumab and steroids were used in 72% and 25% of patients, respectively. Infections were seen in 34% of patients. Day 30 response was evaluable in 104 patients. Response rates were: ≥ partial response, 83%; ≥ very good partial response, 64%; and ≥ complete response (CR), 34%. 11% of patients have died by data cut-off, 7 due to disease progression and 5 due to other causes (1 grade 5 CRS, 1 hemophagocytic lymphohistiocytosis, 1 progressive neurological weakness, 2 COVID-19). Conclusions: This multicenter retrospective study delineates the real-world outcomes of ide-cel CAR T-cell therapy for RRMM. Despite more patients being penta-refractory and less fit compared to the pivotal KarMMa trial, safety and 30-day responses in the real-world setting (overall response rate: 83%, CR: 34%) are comparable to the clinical trial population. Follow-up is ongoing and updated data will be presented. [Table: see text]
WNK463 and HTH01-015 simultaneously inhibit neurogenic and α1-blocker-resistant, non-adrenergic contractions of human prostate tissues, and growth-related functions of prostate stromal cells
Authors: Y. Liu, R. Huang, B. Li, R. Wang, A. Tamalunas, R. Waidelich, F. Strittmatter, C.G. Stief, M. Hennenberg
Journal: European Urology (2022)
Safety and immunogenicity of a live-attenuated influenza virus vector-based intranasal SARS-CoV-2 vaccine in adults: randomised, double-blind, placebo-controlled, phase 1 and 2 trials
Authors: Fengcai Zhu, Chunlan Zhuang, Kai Chu, Liang Zhang, Hui Zhao, Shoujie Huang, Yingying Su, Hongyan Lin, Changlin Yang, Hanmin Jiang, Xia Zang, Donglin Liu, Hongxing Pan, Yuemei Hu, Xiaohui Liu, Qi Chen, Qiaoqiao Song, Jiali Quan, Zehong Huang, Guohua Zhong, Junyu Chen, Jinle Han, Hong Sun, Lunbiao Cui, Jingxin Li, Yixin Chen, Tianying Zhang, Xiangzhong Ye, Changgui Li, Ting Wu, Jun Zhang, Ning-Shao Xia
Journal: The Lancet Respiratory Medicine (2022)
Simultaneous analysis of serum α2,3-linked sialylation and core-type fucosylation of prostate-specific antigen for the detection of high-grade prostate cancer
Authors: K. Hatano, T. Yoneyama, S. Hatakeyama, E. Tomiyama, M. Tsuchiya, M. Nishimoto, K. Yoshimura, E. Miyoshi, H. Uemura, C. Ohyama, N. Nonomura, K. Fujita
Journal: European Urology (2022)
Protective effects of regulatory T cells in renal ischemia/reperfusion injury in mice
Authors: R. Yamamoto, M. Saito, Y. Aoyama, R. Sagehashi, T. Saito, S. Kashima, A. Koizumi, T. Nara, K. Numakura, S. Narita, S. Satoh, T. Habuchi
Journal: European Urology (2022)
Saraf implication in the vascular remodeling
Authors: M Martin Bornez, JA Rosado, A Ordonez, T Smani
Journal: Cardiovascular Research (2022)

Abstract Funding Acknowledgements Type of funding sources: Public Institution(s). Main funding source(s): Agencia Estatal de Investigación Background Orai1 and STIM1, molecular components of Store-Operated Calcium Entry (SOCE), have been associated with vascular smooth muscle cells (VSMCs) proliferation in vascular remodeling. Nevertheless, the role of SARAF (SOCE Associated Regulatory Factor), a regulatory protein involved in STIM1 inhibition, has not been firmly established in the vascular remodeling. Objetive The aim of this study was to examine the role of SARAF and Orai1 in VSMCs proliferation and neointima formation after balloon injury of rat carotid arteries. Methods and Results Experiments were conducted in an animal model of rat carotid angioplasty to characterize neointima formation. VSMC isolated from rat coronary artery was also used to examine cell proliferation. The formation of neointima after balloon injury of rat carotid arteries was confirmed by haematoxylin and eosin staining of tissue sections up to 3 weeks after surgery. Injured arteries showed significant higher expression of SARAF, STIM1 and Orai1 compared to control tissues, corroborating the presence of these regulatory proteins in the neointima layer. Proximity ligation and co-immunoprecipitation assays revealed that SARAF interacts with Orai1 in the neointima. Furthermore, selective silencing of SARAF and Orai1 by small interfering RNA (siRNA) inhibited VSMC proliferation. Conclusions Our data suggest that SARAF is involved in VSMC proliferation and neointima formation after vascular injury.
Comparison of different treatment modalities for favorable risk acute myeloid leukemia: Standard-dose anthracycline versus high-dose anthracycline versus addition of gemtuzumab ozogamicin.
Authors: Joseph Mort, Leah Wells, Samantha DiBenedetto, Emily Morse, Ben Mautner, Farid Ghamsari, Eric Pierce, Amy Morris, Michael Kenneth Keng, Firas El Chaer
Journal: Journal of Clinical Oncology (2022)

e19016 Background: The standard remission induction regimen for medically fit patients with AML consists of a backbone of cytarabine &amp; an anthracycline (“7+3” therapy). However, the choice &amp; dose of the anthracycline varies between institutions &amp; practitioner preference, particularly in patients with favorable risk cytogenetics. Gemtuzumab ozogamicin (GO) may improve outcomes in this patient population but is associated with increased toxicities. Methods: We performed a retrospective analysis on medically fit patients ≥ 18 yo with favorable risk AML from 2015-2020 treated with 7+3 at the University of Virginia. Patients were stratified based on standard dose (45 or 60 mg/m 2 daunorubicin) (SD) vs higher dose (90 mg/m 2 daunorubicin or 12 mg/m 2 idarubicin) (HD) of anthracycline vs the addition of GO. Measures included rates of remission, EFS, RFS, and OS as well as rates of treatment-related complications. Results: In total, 58 patients were identified, of which 33 received induction with SD, 19 received HD, &amp; 6 received GO. The majority (75%) of patients were &lt; 60 years old &amp; 93% had de novo AML. The rates of complete remission in the SD, HD &amp; GO groups were 90.9%, 89.5% &amp; 100%, respectively (p = 0.57). EFS at 2-years was 43.9%, 36.7%, &amp; 66.7%, respectively (p = 0.85). RFS at 2-years was 53.0%, 39.0%, &amp; 100%, respectively (p = 0.18). OS at 2-years was similar between all groups (58.9%, 56.9%, &amp; 66.7%, p = 0.92). The rate &amp; duration of cytopenias after induction were similar among all groups (median duration 29 days), however cytopenias were more common in the GO group following consolidation. The rates of major bleeding, admission to the intensive care unit (ICU), and new onset cardiomyopathy (EF &lt; 50%) were higher in the GO group (major bleeding: 0% in SD, 5.3% in HD, 33.3% in GO; ICU admission: 12.1% in SD, 21.1% in HD, 33.3% in GO; cardiomyopathy: 12.1% in SD, 26.3% in HD, 33.3% in GO). The rate of infection, liver dysfunction, &amp; acute renal injury were similar among all groups. No patients developed veno-occlusive disease. Conclusions: Patients receiving GO had a trend toward improved EFS &amp; RFS, however with a similar OS at the expense of higher rates of cytopenias, major bleeding, ICU admission, &amp; cardiotoxicity. Patients receiving HD had a trend toward worse outcomes than those who received SD. A major limitation of our study is the small sample size &amp; single institution experience, however multi-institutional analysis is ongoing for further investigation.[Table: see text]
Trial in progress: Phase 3 study of bemarituzumab + mFOLFOX6 versus placebo + mFOLFOX6 in previously untreated advanced gastric or gastroesophageal junction (GEJ) cancer with FGFR2b overexpression (FORTITUDE-101).
Authors: Elizabeth Catherine Smyth, Joseph Chao, Kei Muro, Priscilla Yen, Rolando Eduardo Yanes, Anita Zahlten-Kumeli, Sun Young Rha
Journal: Journal of Clinical Oncology (2022)

TPS4164 Background: Fibroblast growth factor receptor 2b (FGFR2b) is overexpressed in approximately 30% of non-human epidermal growth factor receptor 2 (non-HER2) positive gastric cancer (Wainberg, 2021). Bemarituzumab is a first-in-class monoclonal antibody that specifically blocks FGFR2b, inhibiting downstream tumor proliferation and enhancing antibody-dependent cellular cytotoxicity (Catenacci, 2020; Xiang, 2021). In the phase 2 FIGHT study (Wainberg, 2021; Catenacci, 2021), bemarituzumab + mFOLFOX6 improved progression-free survival (PFS; HR, 0.68; 95% CI, 0.44‒1.04; p = 0.07) and led to a 5.7 month longer median overall survival (OS; 19.2 months vs 13.5 months; HR, 0.60; 95% CI, 0.38-0.94) compared with placebo + mFOLFOX6. Methods: FORTITUDE-101 (NCT05052801) is a double-blind, placebo-controlled phase 3 study in patients with untreated, unresectable locally advanced or metastatic gastric or GEJ adenocarcinoma not amenable to curative therapy. Approximately 516 patients aged ≥18 years with IHC-confirmed FGFR2b overexpression by central testing will be enrolled and randomized 1:1 to bemarituzumab + mFOLFOX6 or placebo + mFOLFOX6. Additional key eligibility criteria include Eastern Cooperative Oncology Group performance status 0-1, evaluable disease per RECIST v1.1, adequate hematologic and organ function, and no contraindication to receive mFOLFOX6 chemotherapy. Key exclusion criteria include prior treatment for metastatic or unresectable disease except one dose of mFOLFOX6 during screening, positive HER2 status, untreated or symptomatic CNS metastasis and leptomeningeal disease, history or evidence of ongoing ophthalmologic abnormalities, and prior treatment with any FGF-FGFR pathway inhibitor. Patients randomized to bemarituzumab will receive 15 mg/kg every 2 weeks (Q2W) with an additional 7.5 mg/kg dose on cycle 1 day 8. mFOLFOX6 will be administered at a fixed dose Q2W. Patients will receive treatment until disease progression, unacceptable toxicity, withdrawal of consent, or death. The primary endpoint is OS; secondary endpoints include PFS, objective response (defined as best overall response of complete or partial response), and treatment-emergent adverse events. Tumor responses and PFS will be assessed locally per RECIST v1.1. The concurrent phase 1b/3 FORTITUDE-102 study (NCT05111626) will evaluate the efficacy and safety of bemarituzumab + mFOLFOX6 + nivolumab versus placebo + mFOLFOX6 + nivolumab. Clinical trial information: NCT05052801.
Results from the phase 1/2 study of patritumab deruxtecan, a HER3-directed antibody-drug conjugate (ADC), in patients with HER3-expressing metastatic breast cancer (MBC).
Authors: Ian E. Krop, Norikazu Masuda, Toru Mukohara, Shunji Takahashi, Takahiro Nakayama, Kenichi Inoue, Hiroji Iwata, Tatsuya Toyama, Yutaka Yamamoto, Damien Mikael Hansra, Masato Takahashi, Akihiko Osaki, Kumiko Koyama, Tatsuya Inoue, Takatoshi Yonekura, Joseph Mostillo, Shoichi Ohwada, Yoshimi Tanaka, David W. Sternberg, Kan Yonemori
Journal: Journal of Clinical Oncology (2022)

1002 Background: Patritumab deruxtecan (HER3-DXd) is a novel, investigational ADC composed of a human anti-HER3 monoclonal antibody covalently bound to a topoisomerase I inhibitor payload via a stable tetrapeptide-based cleavable linker. Here we report updated safety and efficacy data from this ongoing study (U31402-A-J101; NCT02980341; JapicCTI-163401) of HER3-DXd in pts with previously treated MBC. Methods: U31402-A-J101 is a phase 1/2, multicenter, open-label, first-in-human study of HER3-DXd in pts with HER3-expressing MBC (N = 182). The study enrolled pts in dose-escalation (3.2-8.0 mg/kg IV Q3W) and dose-finding portions across molecular subtypes (n = 66; including HER2+ MBC, n = 14) followed by dose expansion in the following subtypes: HER3 high (4.8 mg/kg [n = 33] or 6.4 mg/kg [n = 31]), HER3 low (6.4 mg/kg [n = 21]) HR+/HER2− MBC or HER3-high TNBC (6.4 mg/kg [n = 31]). HER3-high and -low were defined as ≥75% and 25% ‒ &lt; 75% membrane positivity. The primary objective was to assess safety and efficacy; secondary objectives included determining the relationship between efficacy and HER3 expression. Results: At data cutoff (16 Aug 2021), median study duration was 31.9 mo (range, 15-56). Median age was 57 y (range, 30-83); 132 (72.5%) and 50 (27.5%) pts had an ECOG PS of 0 or 1. Pts had a median of 5 (range, 1-13) prior lines of therapy for locally advanced/metastatic disease. Median treatment duration with HER3-DXd was 5.9 mo (range, 0.7-30.6). In a pooled evaluation of dose escalation/finding and expansion, efficacy is shown in pts with HR+/HER2− MBC, TNBC, and HER2+ MBC in the Table. Overall, 130 pts (71.4%) had grade ≥3 TEAEs; the most common (≥15%) were decreased neutrophil count (39.6%), decreased platelet count (30.8%), anemia (18.7%), and decreased white blood cell count (18.1%). 12 pts (6.6%) experienced treatment-related interstitial lung disease according to central adjudication, including 1 grade 5 event. Conclusions: A pooled analysis in this heavily pretreated population showed promising efficacy in pts with HR+/HER2− and HER2+ MBC as well as TNBC. The safety profile with longer follow-up is consistent with previous reports and showed adequate safety and tolerability. Studies are ongoing in MBC tumor types, with a focus on biomarkers associated with efficacy. Clinical trial information: NCT02980341. [Table: see text]
DIPG-20. Copper chelation therapy targets S-adenosylmethionine (SAM) metabolism and epigenetic regulators in diffuse intrinsic pontine glioma (DIPG)
Authors: Filip Michniewicz, Jessica Bell, Federica Saletta, Tayla Watkinson, Daniele Mercatelli, Federico M Giorgi, Christopher K Barlow, Pouya Faridi, Maria Tsoli, David Ziegler, Orazio Vittorio
Journal: Neuro-Oncology (2022)

Abstract DIPG is an incurable pediatric brain cancer of the ventral pons characterized by its complex epigenetic profile. Up to 81% of patients present with mutation H3K27M, resulting in the global reduction of H3K27 trimethylation and increased H3K27 acetylation, deregulating gene expression through an aberrant pattern of epigenetic modification. These alterations affect many cellular and metabolic mechanisms, complicating the search for effective targeted therapeutic strategies. Copper is highly abundant in the pons and is essential for normal brain function and development. However, excess copper accumulation is implicated in several neurological diseases and cancers. Incidentally, recent investigations have indicated the H3-H4 dimer can interact with copper acting as a reductase enzyme. Copper chelation therapy is clinically approved for pediatric patients with Wilson’s Disease, improving their neurological symptoms, and is being trialed in several cancers. We therefore hypothesized copper chelation may represent an effective therapeutic strategy for DIPG. Copper chelator tetraethylenepentamine (TEPA) decreased cell growth and induced apoptosis in DIPG cell lines. To understand these results, unbiased RNA-seq and metabolomics analyses were performed, revealing downregulation of EZH2, DNMT1 and DNMT3B, upregulation of KDM6B and the disruption of key enzymes in the S-adenosylmethionine (SAM)-cycle. Importantly, TEPA downregulated SAM, which donates methyl groups for methylation, S-adenosylhomocysteine, its post-methylation product and α-ketoglutarate, a co-factor for KDM6B. Western blots confirmed the reduced expression of EZH2, DNMT1 and DNMT3B, with further blots examining the chromatin cell fraction revealing modulation of H3K27 trimethylation through copper or TEPA stimulation, and reduction of H3K27 acetylation by TEPA. Importantly, in vitro combinations with Panobinostat were synergistic, while in vivo investigations demonstrated TEPA improved survival in an orthotopic patient derived xenograft (PDX) model, showing complete tumor regression in 25% of treated mice. This study indicates a novel use for copper chelators as epigenetic drugs, and their potential as therapeutics for DIPG.